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Tumour evolution

Clonal ancestry in lung cancer

Nature Reviews Cancer volume 14, page 763 (2014)Cite this article

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de Bruin, McGranahan, Mitter, Salm, Wedge and colleagues carried out multiregion whole-exome sequencing (WES) and whole-genome sequencing (WGS) of 25 tumour samples from 7 patients with NSCLC. They identified 1,884 non-synonymous mutations, and these were classified according to whether they were ubiquitous in all tumour regions or occurred heterogeneously. Spatial intratumoural heterogeneity was observed to different extents in all patients, so the authors constructed phylogenetic trees for each tumour on the basis of the clonal (or truncal) and subclonal (or branched) mutations, and of regional copy number alterations (CNAs); branched evolution was evident in all of the tumours.

de Bruin et al. found that there were instances of heterogeneous occurrence of driver mutations such that some mutations were dominant only in some tumour regions from the same patient. This raises the important issue that sequencing different regions of a tumour may lead to different conclusions about driver mutations and candidate therapeutic targets. Nonetheless, driver mutations were mostly ubiquitous, indicating that these alterations occur early in tumour evolution. Analyses of CNAs indicated that they were mostly heterogeneous and therefore occur later in tumour evolution. de Bruin et al. also assessed the mutation spectra in the tumour samples. They found that the mutation spectra significantly changed temporally for all tumours. In particular, the proportion of C-to-A transversion mutations — which are associated with exposure to tobacco smoke — decreased as the tumours evolved, and this was confirmed using sequencing data from a larger cohort of NSCLC samples. The decrease in the proportion of C-to-A mutations was least or absent in current smokers with squamous cell carcinoma NSCLC. As the proportion of C-to-A transversions decreased, the authors noted an increase in the proportions of C-to-T and C-to-G mutations in mutation spectra that are associated with the cytidine deaminase activity of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes. APOBEC-associated mutations were mostly subclonal, indicating that APOBEC-mediated mutagenesis is involved in the progression of adenocarcinoma NSCLCs and, less clearly, of squamous cell carcinoma NSCLCs.

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References

  1. de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014)

    Article  CAS  Google Scholar 

  2. Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014)

    Article  CAS  Google Scholar 

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  1. Gemma K. Alderton
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Westcott, P. M. K. et al. The mutational lanscapes of genetic and chemical models of Kras-driven lung cancer. Nature (2014)

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Alderton, G. Clonal ancestry in lung cancer. Nat Rev Cancer 14, 763 (2014). https://doi.org/10.1038/nrc3867

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